Topical administration of at least one double-stranded RNA oligonucleotide (dsRNA)

Abstract

Expression of a messenger RNA which encodes a protein which is expressed by differentiated cells, notably the cells of the skin or appendages thereof, is inhibited by topically administering to said differentiated cells a thus effective amount of at least one double-stranded RNA oligonucleotide, formulated into a topically applicable, physiologically acceptable medium therefor; such regime or regimen is useful for treating a variety of afflictions or conditions, e.g., combating the signs of skin aging, stimulating hair growth or retarding loss thereof, inhibiting cellular proliferation and/or differentiation, etc.

1 . A regime or regimen for inhibiting the expression of a messenger RNA which encodes a protein which is expressed by differentiated cells, comprising topically administering to said differentiated cells a thus effective amount of at least one double-stranded RNA oligonucleotide, formulated into a topically applicable, physiologically acceptable medium therefor.  
     
     
         2 . A regime or regimen for inhibiting the expression of a messenger RNA which encodes a protein which is expressed by differentiated cells of the skin or appendages thereof, comprising topically administering to said differentiated cells of the skin or appendages thereof a thus effective amount of at least one double-stranded RNA oligonucleotide, formulated into a topically applicable, physiologically acceptable medium therefor.  
     
     
         3 . The regime or regimen as defined by  claim 2 , said at least one double-stranded RNA oligonucleotide comprising at least 10 nucleotides.  
     
     
         4 . The regime or regimen as defined by  claim 2 , said at least one double-stranded RNA oligonucleotide comprising from 12 to 40 nucleotides.  
     
     
         5 . The regime or regimen as defined by  claim 2 , said at least one double-stranded RNA oligonucleotide comprising from 20 to 25 nucleotides.  
     
     
         6 . The regime or regimen as defined by  claim 2 , said at least one double-stranded RNA oligonucleotide comprising from 21 to 23 nucleotides.  
     
     
         7 . The regime or regimen as defined by  claim 2 , said at least one double-stranded RNA oligonucleotide having been obtained by the folding and pairing of a self-complementary RNA single strand.  
     
     
         8 . The regime or regimen as defined by  claim 2 , said at least one double-stranded RNA oligonucleotide having unpaired ends of from 2 to 6 nucleotides in length.  
     
     
         9 . A regime or regimen as defined by  claim 2  for depigmenting and/or bleaching the skin or the hair and nails of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes tyrosinase and/or TRP-1.  
     
     
         10 . A regime or regimen as defined by  claim 2  for preventing and/or combating cutaneous signs of aging of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes neutrophil elastase and/or hyaluronidase and/or a metalloproteinase and/or HMG-CoA reductase and/or calmodulin-like skin protein (CLSP) and/or NO synthase.  
     
     
         11 . A regime or regimen as defined by  claim 2  for inducing and/or stimulating growth of head hair and/or body hair and/or retarding loss of head hair of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes a metalloprotease and/or type I or type II 5α-reductase and/or NO synthase.  
     
     
         12 . A regime or regimen as defined by  claim 2  for preventing and/or combating the loss of firmness and/or suppleness of the skin and/or atropy of the skin and/or the formation of wrinkles and fine lines of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes the enzyme neutrophil elastase, hyaluronidase or a metalloprotease.  
     
     
         13 . A regime or regimen as defined by  claim 2  for preventing and/or combating excessive production of sebum or sweat in the region of the armpits or the feet of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes HMG-COA reductase.  
     
     
         14 . A regime or regimen as defined by  claim 2  for treating an androgen-dependent disorder of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes type I α-reductase.  
     
     
         15 . A regime or regimen as defined by  claim 2  for treating hyperseborrhea and/or acne of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes type I α-reductase.  
     
     
         16 . A regime or regimen as defined by  claim 2  for combating the harmful effects of ultraviolet radiation and/or treating dry skin of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes calmodulin-like skin protein (CLSP).  
     
     
         17 . A regime or regimen as defined by  claim 2  for inhibiting cellular proliferation and/or differentiation and/or inhibiting the breakdown and/or destruction of the cells of the skin of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes NO synthase.  
     
     
         18 . A regime or regimen as defined by  claim 2  for treating sensitive skin and erythemas of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes NO synthase.  
     
     
         19 . A regime or regimen for inhibiting the expression of a messenger RNA which encodes a protein which is expressed by differentiated cells of a eukaryotic microorganism on the surface of the skin or appendages thereof, comprising topically administering to said differentiated cells of said eukaryotic microorganism a thus effective amount of at least one double-stranded RNA oligonucleotide, formulated into a topically applicable, physiologically acceptable medium therefor.  
     
     
         20 . A regime or regimen as defined by  claim 2  for inhibiting the expression of a messenger RNA which encodes a protein expressed by melanocytes and/or keratinocytes and/or fibroblasts and/or endothelial cells and/or resident immune cells.  
     
     
         21 . A regime or regimen as defined by  claim 2  for inhibiting the expression of a messenger RNA which encodes a protein selected from the group consisting of tyrosinase, TRP-1 (tyrosinase-related protein 1), the enzyme neutophil elastase, hyaluronidase, a metalloproteinase, HMG-CoA reductase, type I or type II 5α-reductase, calmodulin-like skin protein (CLSP), NO synthase, urokiinase, cyclooxygenases, lipoxygenases, phospholipases, 15-PGDH, enzymes of hormonal metabolism, type I or type II 5α-reductase, matrix proteins of the elastin or collagen type, keratinocyte differentiation proteins of the cytokeratin type, proteins involved in moisturization of the skin, filaggrin, aquaporins, a serine protease, a cytokine, a growth factor, a protein or a peptide of morphogenesis, proteins involved in the antibacterial defenses of the skin, hBD2, hBD3, dermcidin, RNase 7.  
     
     
         22 . A regime or regimen as defined by  claim 2  for inhibiting the expression of a messenger RNA which encodes a protein of a eukaryotic microorganism selected from the group consisting of squalene epoxidase,  C. albicans  cytochrome P450-dependent 14-alpha sterol demethylase, proteins for detoxifying antimycotic agents, trichophyton rubrum esterases, aspartic proteinases, phospholipase D,  Candida  phospholipase B, 2,3-oxidosqualene cyclases, 22,23-epoxy-2-aza-2,3-dihydrosqualene (EAS) and azasqualene alcohol (ASA).  
     
     
         23 . A regime or regimen as defined by  claim 2  for treating psoriasis of an individual in need of such treatment, said at least one double-stranded RNA oligonucleotide inhibiting the expression of a messenger RNA which encodes a metalloprotease and/or a detoxification protein.  
     
     
         24 . A topically applicable cosmetic/dermatological composition, comprising an amount of at least one double-stranded RNA oligonucleotide effective, when administered to an individual in need of such treatment, for inhibiting the expression of a messenger RNA which encodes a protein which is expressed by differentiated cells, formulated into a topically applicable, physiologically acceptable medium therefor.  
     
     
         25 . The topically applicable cosmetic/dermatological composition as defined by  claim 24 , said at least one double-stranded RNA oligonucleotide comprising from 5.10 −7  to 5% by weight thereof.  
     
     
         26 . The topically applicable cosmetic/dermatological composition as defined by  claim 24 , said at least one double-stranded RNA oligonucleotide comprising a complex thereof.  
     
     
         27 . The topically applicable cosmetic/dermatological composition as defined by  claim 24 , said at least one double-stranded RNA oligonucleotide being confined in the core or a wall of a delivery vehicle therefor.  
     
     
         28 . The topically applicable cosmetic/dermatological composition as defined by  claim 27 , said at least one double-stranded RNA oligonucleotide being encapsulated in the core or the wall of microspheres, nanospheres, oleosomes, niosomes or nanocapsules.  
     
     
         29 . The topically applicable cosmetic/dermatological composition as defined by  claim 24 , formulated as an aqueous or oily solution, emulsion, gel, paste, solid, cream, ointment, milk, lotion, serum, mousse or aerosol.  
     
     
         30 . The topically applicable cosmetic/dermatological composition as defined by  claim 24 , confined on a microneedle patch.  
     
     
         31 . The topically applicable cosmetic/dermatological composition as defined by  claim 24 , said at least one double-stranded RNA oligonucleotide comprising two of the sequences selected from the group consisting of:  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   5′-UGCACCACUUGGGCCUCAAdTdT,: 
                   SEQ ID no.1 
                     
                 
                     
                     
                 
                     
                   5′-UUGAGGCCCAAGUGGUGCAdTdT,: 
                   SEQ ID no.2 
                 
                     
                     
                 
                     
                   5′-CGGCUACGACCCCGUAAACdTdT,: 
                   SEQ ID no.3 
                 
                     
                     
                 
                     
                   5′-GUUUACGGGGUCGUAGCCGdTdT,: 
                   SEQ ID no.4 
                 
                     
                     
                 
                     
                   5′-AGCCGCGAGGGUCGUCCAAdTdT,: 
                   SEQ ID no.5 
                 
                     
                     
                 
                     
                   5′-UUGGACGACCCUCGCGGCUdTdT,: 
                   SEQ ID no.6 
                 
                     
                     
                 
                     
                   5′-CUGCAUCCUCCUGGCCAUGdTdT,: 
                   SEQ ID no.7 
                 
                     
                     
                 
                     
                   5′-CAUGGCCAGGAGGAUGCAGdTdT,: 
                   SEQ ID no.8 
                 
                     
                     
                 
                     
                   5′-GGCUUUCUCCGCGGUUGACdTdT,: 
                   SEQ ID no.9 
                 
                     
                     
                 
                     
                   5′-GUCAACCGCGGAGAAAGCCdTdT,: 
                   SEQ ID no.10 
                 
                     
                     
                 
                     
                   5′-AAGUGUUUGAUGCUGGAGGdTdT,: 
                   SEQ ID no.11 
                 
                     
                     
                 
                     
                   5′-CCUCCAGCAUCAAACACUUdTdT,: 
                   SEQ ID no.12 
                 
                     
                     
                 
                     
                   5′-GCACCAGCUUUUCUGCCUUdTdT,: 
                   SEQ ID no.13 
                 
                     
                     
                 
                     
                   5′-AAGGCAGAAAAGCUGGUGCdTdT,: 
                   SEQ ID no.14 
                 
                     
                     
                 
                     
                   5′-ACUGCACAGAGAGACGACUdTdT,: 
                   SEQ ID no.15 
                 
                     
                     
                 
                     
                   5′-AGUCGUCUCUCUGUGCAGUdTdT,: 
                   SEQ ID no.16 
                 
                     
                     
                 
                     
                   5′-GCACCAGCUUUUCUGCCUUdTdT,: 
                   SEQ ID no.17 
                 
                     
                     
                 
                     
                   5′-AAGGCAGAAAAGCUGGUGCdTdT,: 
                   SEQ ID no.18 
                 
                     
                     
                 
                     
                   5′-AGCAGCAUGCACAAUGCCUdTdT,: 
                   SEQ ID no.19 
                 
                     
                     
                 
                     
                   5′-AGGCAUUGUGCAUGCUGCUdTdT,: 
                   SEQ ID no.20 
                 
                     
                     
                 
                     
                   5′-AGCCUGACCUCACUCUAACdTdT,: 
                   SEQ ID no.21 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   5′-GUUAGAGUGAGGUCAGGCUdTdT,: 
                   SEQ ID no.22